Modular actin nano-architecture enables podosome protrusion and mechanosensing

Abstract

Basement membrane transmigration during embryonal development, tissue homeostasis and tumor invasion relies on invadosomes, a collective term for invadopodia and podosomes. An adequate structural framework for this process is still missing. Here, we reveal the modular actin nano-architecture that enables podosome protrusion and mechanosensing. The podosome protrusive core contains a central branched actin module encased by a linear actin module, each harboring specific actin interactors and actin isoforms. From the core, two actin modules radiate: ventral filaments bound by vinculin and connected to the plasma membrane and dorsal interpodosomal filaments crosslinked by myosin IIA. On stiff substrates, the actin modules mediate long-range substrate exploration, associated with degradative behavior. On compliant substrates, the vinculinbound ventral actin filaments shorten, resulting in short-range connectivity and a focally protrusive, non-degradative state. Our findings redefine podosome nanoscale architecture and reveal a paradigm for how actin modularity drives invadosome mechanosensing in cells that breach tissue boundaries. Podosomes | Mechanosensing | Actin architecture | Cytoskeleton | Superresolution Correspondence: Alessandra.Cambi@radboudumc.nl van den Dries et al. | bioRχiv | March 18, 2019 | 1-17

B cells extract antigens at Arp2/3-generated actin foci interspersed with linear filaments

“…In this model, stochastic Arp2/3 activation produces actin foci by local bursts of branching of preexisting short filaments. Branched actin polymerization may either push on the membrane to generate protrusions, similarly as it happens in podosomes (van den Dries et al, 2019), or synergize with BCR-dependent signaling and endocytic proteins to produce an invagination of the plasma membrane and extract the antigen. Formin-generated filaments may stabilize the foci by surrounding and connecting them, which, along with crosslinking and tensioning by myosin IIa, could help to direct the foci-generated forces perpendicularly to the plasma membrane.…”

Crosstalk between Cell Adhesion Complexes in Regulation of Mechanotransduction

“…Super-resolution microscopy analysis of the podosome architecture shows that both vinculin and myosin II are linked to actin filaments in the podosomal ring and that these proteins and their associated actin filaments form two separate modules surrounding the actin core. [55] This organization of integrins, mechanosensitive proteins, actin, and myosin in podosomes thus differs from FAs, in which talin/vinculin directly connect integrins to actomyosin cytoskeleton. Invadosomes can form under low cellular tension, since they are driven by actin polymerization, and might act as mechanosensors by integrins that pull on the ECM adjacent to the protrusive actin core.…”

Megakaryocytes use in vivo podosome‐like structures working collectively to penetrate the endothelial barrier of bone marrow sinusoids

“…The to produce protrusive forces. 29,30,32 To investigate the role of the myosin II-enriched network, we used mice in which the Myh9 gene was specifically inactivated in the MK lineage (Myh9 -/mice). We previously reported that these mice are thrombocytopenic (336 × 10 9…”